hepatic physiology sabina sabharwal, md mph boston childrens hospital content reviewers karen...
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Outline Anatomy and blood supply of the liver Physiologic immaturity of hepatic function Mechanisms of hepatic regeneration Hepatic serum protein synthesis Hepatic carbohydrate metabolism Hepatic fatty acid metabolism Biochemical parameters of hepatic integrity Pathways of hepatic drug metabolism Bilirubin uptake, metabolism, excretion Portal hypertension Board review questionsTRANSCRIPT
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Hepatic Physiology
Sabina Sabharwal, MD MPHBoston Children’s Hospital
Content Reviewers
Karen Murray, MDDavid Piccoli, MD
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NASPGHAN Physiology Education Series
Series Editors:Christine Waasdorp Hurtado, MD, MSCS, [email protected] Daniel Kamin, [email protected]
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Outline• Anatomy and blood supply of the liver• Physiologic immaturity of hepatic function• Mechanisms of hepatic regeneration• Hepatic serum protein synthesis• Hepatic carbohydrate metabolism• Hepatic fatty acid metabolism• Biochemical parameters of hepatic integrity• Pathways of hepatic drug metabolism• Bilirubin uptake, metabolism, excretion• Portal hypertension• Board review questions
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Segmental anatomy of the liver
• Couinaud (“French” system) – based on tranverse plane through bifurcation of mail
portal vein– Functional lobes divided into total of 8 subsegments
• Caudate 1• Lateral 2,3• Medial 4a, 4b• Right 5,6,7,8
– Caudate lobe is separate, receiving blood flow from R and L -sided vasculature
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Blood supply liver• Hepatic artery (25%) – oxygenated• Hepatic portal vein (75%) – deoxygenated blood,
nutrient- rich• Oxygen comes equally form both sources• Terminal branches of hepatic portal vein and hepatic
artery empty together and mix entering the liver• Blood flows through liver sinusoids, empties into
central vein of each lobule• Central veins coalesce into hepatic veins• Blood exits liver via hepatic vein and returns to the
heart via IVC, deoxygenated and detoxified
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Blood supply and segments of the liver
From Dancygier Clinical Hepatology, Chapter 2. In SpringerImages database (non-commercial use permitted)
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Extramedullary hematopoiesis
• Until 32 weeks of gestation in fetal development, hematopoiesis occurs primarily by the liver (and also the spleen)
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Physiologic Immaturity of hepatic function
• Full maturity of biliary secretion takes up to 2 years after birth to be achieved
• Involves normal expression of signalling pathways including JAG1 genes, amino acid transport, insulin growth factors
• Hepatocytes are specialized at birth with 2 surfaces:– Sinusoidal surface absorbs mixture of oxygenated
blood and nutrients from portal vein– Other surface delivers bile and products of
conjugation, metabolism to bile canaliculi
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Physiologic Immaturity of hepatic function
• With interruption of umbilical supply at birth, rapid induction of transamination, glutamyl transferase, coagulation factor synthesis, bile production and transport
• Preterm infants have immaturity and delay in achieving normal detoxifying and synthetic function, risk of hypoxia and sepsis – all placing them at risk for hepatic decompensation
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Lobule and its zones
• 3 distinct zones of the hepatic acinus:– Zone 1: periportal hepatocytes
• Hepatocyte regeneration• Bile duct proliferation• gluconeogenesis
– Zone 2: mixed function between zones 1 and 3– Zone 3: borders central vein
• Detoxification• Glyocolysis• Hydrolysis
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From Shih et al. Journal of Biomed Microdevices 2013 in SpringerImages database ((non-commercial use permitted)
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Hepatic Regeneration• In fully developed liver, only 1/10-20,000
hepatocytes are dividing• As little as 25% of liver can regenerate a full liver• If stimulated, the liver can regenerate rapidly:
– Viruses– Cirrhosis– Ischemia– Trauma– Partial hepatectomy
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Hepatic Regeneration
• Requires new hepatocyte recruitment and ECM restoration
• IL-6, epidermal growth factor (EGF), TGF-a, TGF-B hepatocyte growth factor (HGF): initiation and regulation of regeneration
• EGF works with insulin and glucagon to promote hepatocyte DNA synthesis
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Liver Protein synthesis • Plasma proteins
– Alpha-fetoprotein (AFP), fibronectin, C-reactive protein, opsonin, acute phase proteins, globulins
• Hemostasis, fibrinolysis– All coagulation cascade (except factor VIII – endothelium), alpha1
antitrypsin, antithrombin III, protein C and S, plasminogen, complement components
• Hormones, prohormones– IGF-1, thrombopoietin, angiotensinogen
• Carrier proteins – Albumin, ceruloplasmin, transcortin, haptoglobin, hemopexin, IGF
binding protein, retinol binding protein, sex hormone binding globulin, thyroxine-binding globulin, tranferrin, vitamin D binding globulin
• Apolipoproteins– All except apo B48 (intestine)
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Taurine• Conditionally essential amino acid in early life• Essential amino acid for preterm/newborn infants and
assured by breast milk• Diet is usual source, but in presence of vitamin B6,
synthesized from methionine and cysteine• Patients on chronic TPN are at risk of taurine
deficiency and need supplementation• Also at risk are those with hepatic, cardiac and renal
failure• Taurine involved in bile acid conjugation and
cholestasis prevention
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Hepatic carbohydrate metabolism
• Gluconeogenesis– Synthesis of glucose from amino acids, lactate,
glycerol• Glycogenolysis
– Breakdown of glycogen into glucose• Glycogenesis
– Formation of glycogen from glucose
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Fatty acids and lipid transport• Triglycerides absorbed as free fatty acids (FA), packaged in
chylomicrons/liposomes released through lymphatic system into the blood and binding to hepatocytes
• Liver processes chylomicron remnants and liposomes into VLDL and LDL
• FA synthesized by the liver get converted to triglycerides and are transported into the blood as VLDL
• In peripheral tissue, lioprotein lipase converts VLDL to LDL and free FA by removing triglycerides
• The remaining VLDL then becomes LDL, absorbed by LDL receptors• LDL is then converted into free fatty acids, cholesterol• Liver controls serum cholesterol concentration by removal of LDL• HDL carries cholesterol from the body back to the liver to be broken
down and excreted
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Hepatocyte biochemical parameters
• Hepatocellular injury – – membranes of hepatocytes become permeable
when damaged– alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) escape into bloodstream• Cholestasis –
– obstructed/damaged intra- and extra- hepatic bile ducts
– induction of alkaline phosphatase and gamma-glutamyl transferase (GGT)
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Hepatic drug metabolism• Mostly in the smooth endosplasmic reticulum of the liver• Factors that increase and decrease drug biotransformation affect
enzymes in the Cytochrome P450 monooxygenase system• Phase 1 (utilized by acetaminophen and steroids)
– Oxidation: cytochrome P450 and flavin-containing monooxygenase, alcohol and aldehyde dehydrogenase, monoamine oxidase, peroxidase
– Reduction: NADPH P450 reductase, reduced (ferrous) cytochrome P450
– Hydrolysis: esterase, amidase, epoxide hydrolase • Phase 2 (detoxifying)
– Conjugation reactions– Methylation, sulphation, acetylation, glucuronidation, glutathione and
glycine conjugation
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Clinical vignette: acetaminophen toxicity
• Acetaminophen metabolism: normal dose – Phase II metabolism: sulfate and glucuronide
metabolism– Cytochrome P450: only 5% of acetaminophen
converted to NAPQI– NAPQI detoxified via glutathione conjugation to
cysteine and mercapturic acid conjugates
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Clinical vignette: acetaminophen toxicity
• In acetaminophen toxicity:– Phase II metabolism becomes saturated– Shunted to P450 pathway– Glutathione becomes depleted and NAPQI remains in toxic
form– Damages hepatocyte cell membrane and leads to acute
hepatic necrosis– Made worse with chronic alcohol use, concomitant use of
anti-epileptics, large amounts of caffeine– N-acetylcysteine replenishes body stores of glutathione
and is treatment for acetaminophen toxicity
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Bilirubin metabolism
• Formed by breakdown of heme (80% from hemoglobin, 20% from other hemoproteins)
• Heme –via heme oxygenase—biliverdin---via biliverdin reductase---bilirubin IX alpha
• Heme oxygenase is rate-limiting step in bilirubin production
• Heme oxygenase is found in Kupffer cells of the liver and reticuloendothelial cells of the spleen
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Bilirubin metabolism• Albumin binds to bilirubin, reversible except in states
of bilirubin obstruction/conjugated bilirubinemia• Albumin-bilirubin complex dissociates in liver sinusoids
where bilirubin is taken up by hepatocytes• This is via facilitates diffusion, bidirectional• Defects in transporters in these steps cause
hyperbilirubinemia (eg Gilbert’s)• Unconjugated hyperbilirubinemia also results from
cirrhosis when bilirubin produced from the spleen bypasses the liver via portosystemic collaterals
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Bilirubin conjugation
• Bilirubin poorly water soluble because of internal hydrogen bonding which makes it toxic and prevents its elimination
• Glucuronic acid conjugation of bilirubin makes it water-soluble and excretable into bile
• Phototherapy in neonatal jaundice produces configurational and structural bilirubin photoisomers, excreted into bile without further metabolism
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Bilirubin conjugation• Mediated by a family of enzymes called uridine-
diphosphoglucuronate glucuronosyltransferase (UGT)• UGT1A1 is the main enzyme of conjugation• UGT1A1 deficiency – Gilbert’s and Crigler-Najjar
syndromes• Inhibition of UGT1A1 can occur via a factor in breast milk
(breast milk jaundice)• Inhibitory factor from maternal plasma can be transferred
to fetus transplacentally (Lucey Driscoll syndrome) – Inhibits UGT1A1 activity in newborn– Results in unconjugated hyperbilirubinemia
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Bilirubin excretion
• Conjugated bilirubin is excreted in bile across the bile canalicular membrane via active transport
• 4 types of transporters (eg MRP2, ABCC2)• Excretion impaired by viral hepatitis,
cholestasis of pregnancy, Dubin-Johnson and Rotor syndrome
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Bilirubin degradation• 98% of the bile pigment in bile is conjugated and
is water-soluble and will not be absorbed across lipid membrane of small intestinal epithelium
• Unconjugated fraction is partially reabsorbed through enterohepatic circulation
• Bilirubin is reduced by bacterial enzymes in the colon to urobilinoids (urobilinogen and stercobilinogen)
• Intestinal microflora influence serum bilirubin levels and antibiotic use can increase serum bilirubin levels
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From Trowers and Tischler Gastrointestinal Physiology 2014 in SpringerImages database (non-commercial use permitted)
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Bilirubin metabolism in newborns• Generally infants not jaundiced at birth because
placenta can clear bilirubin well from the fetal circulation, but can develop jaundice because– Bilirubin production in term neonates is 2-3 times
higher than adults because they have more red blood cells and the the red blood cells have a shorter life span than in adults
– Bilirubin clearance is decreased in neonates because of UGT1A1 deficiency and does not achieve adult levels until 14 weeks of age
– Neonates have an increase in the enterohepatic circulation of bilirubin
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Clinical vignette: breastmilk jaundice
• Starts at 10-21 days of age (after physiologic jaundice period)
• Effects 0.5-2.4% of newborns• Can last 3-12 weeks• Theory: factor in breast milk is inhibiting
breakdown of bilirubin• As long as infant is feeding and growing and
bilirubin is being monitored, no reason to stop breastfeeding
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Portal hypertension• Portal system definition: begins and ends with
capillaries• Liver portal system: capillaries of intestinal and
splenic mesentery ending in the hepatic sinusoids• Portal hypertension: elevation of portal blood
pressure >5 mm Hg• Because of high prevalence of pediatric biliary
disease compared to adult liver disease, portal hypertension occurs earlier in the course of liver disease versus hepatic insufficiency
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Portal hypertension
Physiologic porto-systemic anastomoses. Portal
circulation in blue, systemic circulation in green
From Moubarak et al. Abdominal Imaging 2012 in SpringerImages database (non-commercial use permitted)
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Portal hypertension
• Combination of increased portal resistance and/or increased portal blood flow– Splenomegaly/hypersplenism – congestion– Esophageal and rectal varices – decompression
through portosystemic collaterals– Decompression leads to hepatic encephalopathy
and hepatopulmonary syndrome– Portal hypertension leads to ascites and
complications: peritonitis and hepatorenal syndrome
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Portal hypertension
• Hepatic encephalopathy– Reversible impairment in neuropsychiatric
function– Pathogenesis unclear
• Increase in ammonia concentration• Inhibitory neurotransmitter through GABA receptors in
the CNS• Changes in central neurotransmitters and amino acids
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Portal Hypertension• Hepatopulmonary syndrome
– Triad: liver disease, impaired oxygenation, intrapulmonary vascular dilatations
• Hepatorenal syndrome– Usually from portal hypertension from cirrhosis, but also
in fulminant hepatic failure– Diagnosis of exclusion of acute renal failure– Associated with poor prognosis– Increasingly severe hepatic injury results in reduction in
renal perfusion
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Summary
• The liver is organized by its vascular supply into segments, and has a unique blood supply that includes arterial and ‘venous’ blood (portal system) draining the intestine, pancreas, and spleen.
• The microscopic functional unit is the liver lobule, composed of hepatocytes, vessels, and bile ducts, organized in a fashion that promotes the functions of the liver.
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Summary-2• The liver produces the majority of serum proteins, ranging in
function from albumin to sex hormone binding proteins to numerous clotting factors.
• Liver glucose storage, breakdown, and generation maintain serum glucose in a physiologic range
• Serum lipoprotein make up and content is heavily influenced by liver synthesis and uptake of lipoproteins.
• Drug metabolism occurs in hepatocytes via phase I and/or phase II enzyme systems– a goal of which is to produce chemical structures which are excretable in the bile.
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Summary-3
• Bilirubin metabolism is a robust example of a waste product biotransformed into a substance that can then be excreted in the bile. Particular enzymes are responsible for bioconversion and transport.
• Portal hypertension is a pathophysiologic state established by the existence or development of resistance to portal blood flow toward the liver.
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Board review question• A 16 year old female presents to the ER with RUQ abdominal pain, nausea
and malaise. She has a history of depression and seizure disorder. AST and ALT are greater than 10,000 IU/L. She admits to taking acetaminophen for a headache the night before. What of the following is true:
• A. checking a serum acetaminophen level before 4 hours of ingestion is generally helpful
• B. Concomitant use of anti-epileptic medications is protective for her liver• C. If the patient has presented less than 8 hours of ingestion, NAC reduces
risk of hepatotoxicity and improves survival• D. all of the above
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Board review question• A 3 day old full term breast-fed infant is noted to have
jaundice. He is otherwise behaving normally and has normal-colored urine and stools. There was no ABO or Rh incompatibility. The most likely reason for the jaundice is:
• A. biliary atresia• B. a factor in the maternal breast milk that is inhibiting
UGT1A1• C. inadequate milk intake and dehydration• D. none of the above